1. Field of the Invention
The invention relates to a process for preparing enantiomerically pure alcohols.
Reductions with microorganisms or enzymes are described in a large number of pulications and patents. Only a few studies have been published on the reduction of ketones with heteroaromatic radicals and specifically with heteroaromatic radicals in the position a to the carbonyl group.
Thus, for example, Davis et al. (Appl. Environ. Microbiol. 48 (1984) 327-331) describe the microbial reduction of pentoxifylline (3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione), a ketone with a heterocycle in the position .gamma. to the carbonyl group, to the corresponding alcohol (3,7-dihydro-3,7-dimethyl-1-(S-hydroxyhexyl)-1H-purine-2,6-dione). Sources of carbon, nitrogen and phosphorus are necessary for reduction with growing microorganisms. Nothing is said about the enantiomeric purity of the resulting alcohol.
Imuta et al. (J. Org. Chem. 43 (1978) 3530-3532) likewise describe the synthesis in moderate yields and enantiomeric purities of pyridylethanol from the corresponding ketones using growing Cryptococcus macerans cultures. Sources of carbon and nitrogen are also necessary for the reduction in this case.
Takeshita et al. describe in Heterocycles 26 (1987) 3051-3054, the reduction of acetylpyridines with Saccharomyces cerevisiae to pyridylethanol in poor yields.
Optimal microbial reduction of ketones should advantageously comply with a number of conditions such as:
1. high enantiomeric purity PA1 2. high chemical yield PA1 3. high selectivity of the enzyme or microorganism PA1 4. small amounts of catalyst (amounts of enzyme or microorganism) PA1 5. good solubility of precursor and product under the reaction conditions PA1 6. good space-time yield PA1 7. easy purification of the products PA1 8. low-cost synthesis PA1 R.sup.1 PA1 R.sup.2 and R.sup.3 PA1 R.sup.4 PA1 which comprises reducing compounds of the formula II where the substituents R.sup.1 to R.sup.4 have the abovementioned meanings ##STR4## PA1 in aqueous solution in the presence of a carbon source and of a microorganism or of a reducing agent, of a cofactor and of an enzyme, to compounds of the formula I. PA1 alkyl branched or unbranched C.sub.1 -C.sub.6 -alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl, PA1 alkoxy branched or unbranched C.sub.1 -C.sub.6 -alkoxy chains such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy, PA1 alkanoyl branched or unbranched C.sub.1 -C.sub.6 -alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1,1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl, 3-methylbutanoyl, 1,1-dimethylpropanoyl, 1,2-dimethylpropanoyl, 2,2-dimethylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoyl, 1,2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1,1-dimethylbutanoyl, 1,2-dimethylbutanoyl, 1,3-dimethylbutanoyl, 2,2-dimethylbutanoyl, 2,3-dimethylbutanoyl, 3,3-dimethylbutanoyl, 1-ethylbutanoyl, 2-ethylbutanoyl, 1,1,2-trimethylpropanoyl, 1,2,2-trimethylpropanoyl, 1-ethyl-1-methylpropanoyl and 1-ethyl-2-methylpropanoyl. PA1 alkyl branched or unbranched C.sub.1 -C.sub.6 -alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl, PA1 alkoxy branched or unbranched C.sub.1 -C.sub.6 -alkoxy chains such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy, PA1 alkanoyl branched or unbranched C.sub.1 -C.sub.6 -alkanoyl chains such as methanoyl, ethanoyl, propanoyl, 1-methylethanoyl, butanoyl, 1-methylpropanoyl, 2-methylpropanoyl, 1,1-dimethylethanoyl, pentanoyl, 1-methylbutanoyl, 2-methylbutanoyl, 3-methylbutanoyl, 1,1-dimethylpropanoyl, 1,2-dimethylpropanoyl, 2,2-dimethylpropanoyl, 1-ethylpropanoyl, hexanoyl, 1-methylpentanoyl, 1,2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, 1,1-dimethylbutanoyl, 1,2-dimethylbutanoyl, 1,3-dimethylbutanoyl, 2,2-dimethylbutanoyl, 2,3-dimethylbutanoyl, 3,3-dimethylbutanoyl, 1-ethylbutanoyl, 2-ethylbutanoyl, 1,1,2-trimethylpropanoyl, 1,2,2-trimethylpropanoyl, 1-ethyl-1-methylpropanoyl and 1-ethyl-2-methylpropanoyl, PA1 alkylthio branched or unbranched C.sub.1 -C.sub.6 -alkylthio chains such as methylthio, ethylthio, n-propylthio, 1-methylethylthio, n-butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, n-pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, n-hexylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio or 1-ethyl-2-methylpropylthio, PA1 alkylsulfinyl branched or unbranched C.sub.1 -C.sub.6 -alkylsulfinyl chains such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl and 1-ethyl-2-methylpropylsulfinyl, PA1 alkylsulfonyl branched or unbranched C.sub.1 -C.sub.6 -alkylsulfonyl chains such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, 1-methylethylsulfonyl, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, n-pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl and 1-ethyl-2-methylpropylsulfonyl. PA1 alkyl branched or unbranched C.sub.1 -C.sub.6 -alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 10 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl, PA1 cycloalkyl branched or unbranched C.sub.3 -C.sub.8 -cycloalkyl chains with 3 to 8 carbon atoms in the ring, which may contain other heteroatoms in the ring or in the alkyl chain, such as N, O or S, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-cyclopropylpentane, 5-cyclopropylpentane, 2-cyclobutylbutane, 2,3-dimethyl-3-cyclopropylpropane or 1-methyl-2-cyclopropylbutane.